This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project is aimed at delineating potential mechanistic differences of co-stimulatory pathways between CD4+ T cells from SIV disease susceptible rhesus macaques (RM) and SIV disease resistant sooty mangabeys (SM), based on the initial observation that adult sooty mangabey CD4+ T cells are resistant to in vitro anergy induction in contrast to rhesus macaques and human CD4+ T cells. Hence peripheral blood na[unreadable]ve and memory CD4+ T cells are obtained and stimulated in vitro to comparatively evaluate pathways including IL-2 synthesis regulation, CREB/CREM and p300 complex assembly, mTOR and cyclin dependent kinase regulation. These studies have recently highlighted a main difference between SIV infected SM and RM in the observation that SM central memory antigen specific T cells fail to upregulate GRAIL, the gene related to anergy in lymphocytes, unlike RM or human central memory cells, therefore preserving the potential of these cells to become potent effectors in the SM monkey. In addition, an extension of previous studies that have identified dysfunction in polo-like kinases in CD4+ T cells from rhesus macaques following SIV infection, recent microarray kinase analyses delineated several differences in cell cycle intermediates between TCR activated CD4 T cells from SM and RM. The most salient ones were a marked increase in Cyclin D3, E2F3, Cdc45/MCM6, Cyclin B and RAD17 in RM CD4+ T cells which affect both the afferent G1-S and the efferent S-G2 cell cycle transition steps. These alterations are likely to promote increased T cell activation, turnover and apoptosis whereas these changes were not seen when comparing CD4 T cells from before and after SIV infection in SM. These studies are likely to open novel therapeutic alternatives based on selective blockade of specific kinases similar to experimental cancer immunotherapies.